Although several immunological reagents have been developed (ex: tumor infiltrating lymphocytes, antigen specific tumor vaccines, etc.) during the last few years which can recognize and kill melanoma cells and have the potential of curing melanoma patients, most patients are resistant to this form of therapy. This resistance is probably dependent upon a complexity of variables affecting the balance between activation of the immune system and growth of tumor cells in vivo and our limited understanding of them. My work is focused on analyzing variables potentially affecting this balance. During the last year we have addressed several phenomena issues related to this topic, specifically: 1) The significance of the genetic polymorphism of HLA in modulating the cellular immune response toward melanoma and we were able to show that melanoma patients are genetically variable according to their ethnical ancestry and this variability may determine, in some cases, their immunologic reactivity toward melanoma associated antigens. 2) The significance of individual variability in natural and vaccine induced immunocompetence against MAA. We were able to provide evidence for in vivo priming of patients T cells against melanoma antigens and the effectiveness of peptide based vaccination protocols in inducing further activation of such lymphocyte populations. 3) The identification of variable related to tumor heterogeneity that could affect tumor/host interaction: in particular we described several mechanisms of tumor escape including aberrations in HLA expression as well as variability in expression of melanoma associated antigens. 4) We are presently investigating the significance of the quality and intensity of epitope directed T cell sensitization versus endogenous processing of melanoma associated antigens with the purpose of broadening our understanding of the phenomenon of immunodominance and its possible clinical relevance.